Characterization of the Molecular Fragment That Is Responsible for Agonism of Pergolide at Serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A Receptors

@article{Grnemann2008CharacterizationOT,
  title={Characterization of the Molecular Fragment That Is Responsible for Agonism of Pergolide at Serotonin 5-Hydroxytryptamine2B and 5-Hydroxytryptamine2A Receptors},
  author={Tilo G{\"o}rnemann and Harald H{\"u}bner and Peter Gmeiner and Reinhard Horowski and Klaus Peter Latt{\'e} and Miroslav Flieger and Heinz H. Pertz},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  year={2008},
  volume={324},
  pages={1136 - 1145}
}
Cardiac-valve regurgitation observed in Parkinson patients treated with the ergoline dopamine receptor agonist 8β-methylthiomethyl-6-propylergoline (pergolide) has been associated with the agonist efficacy of the drug at 5-hydroxytryptamine2B (5-HT2B) receptors. 5-HT2A receptors may also play a role in pergolide-induced cardiac-valve regurgitation. We studied the pharmacological profile of pergolide and eight derivatives in porcine vascular rings endowed with 5-HT2B and 5-HT2A receptors to… 

Figures and Tables from this paper

The Bulky N(6) Substituent of Cabergoline Is Responsible for Agonism of This Drug at 5-Hydroxytryptamine (5-HT)2A and 5-HT2B Receptors and Thus Is a Determinant of Valvular Heart Disease

It is concluded that the bulky N(6) substituent of cabergoline is responsible for 5- HT2AR and 5-HT2BR agonism and the increased ERK1/2 phosphorylation and production of extracellular matrix by Cabergoline are mediated by 5-ht2ARs.

Pharmacological Profile of 2-Bromoterguride at Human Dopamine D2, Porcine Serotonin 5-Hydroxytryptamine 2A, and α2C-Adrenergic Receptors, and Its Antipsychotic-Like Effects in Rats

2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS because of its in vitro and in vivo properties.

Synthesis of novel analogs of cabergoline: improving cardiovascular safety by removing 5-HT2B receptor agonism.

Several analogs of cabergoline are prepared and several that have limited or no agonism at the 5-HT2B receptor agonists are identified.

Dopamine-induced functional activation of Gαq mediated by dopamine D1-like receptor in rat cerebral cortical membranes

Dopamine-stimulated Gαq functionality was highest in cortex as compared to hippocampus or striatum, and the responses induced by SKF83566, R(+)-SCH23390, and pergolide were most likely mediated by 5-HT2A receptor, but not by dopamine D1-like receptor.

Acute pergolide exposure stiffens engineered valve interstitial cell tissues and reduces contractility in vitro.

Cognition and serotonin in Parkinson's disease.

Tactical Approaches to Interconverting GPCR Agonists and Antagonists.

An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing G PCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GpcR of choice.

Trazodone generates m-CPP: In 2008 risks from m-CPP might outweigh benefits of trazodone

  • R. Kast
  • Psychology
    The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry
  • 2009
It is argued that the documented potential for harm and multiple risks of m-CPP outweigh potential benefits of trazodone, given the development and marketing of many safer alternatives since traZodone's introduction in the 1980s.

The role of cell biology and leaflet remodeling in the progression of heart valve disease.

This review addresses current advances in the field of valve biology, mechanisms underlying valvular leaflet remodeling, and common pathological manifestations and underscores the importance of understanding the impact of cardiovascular drugs and remodeling changes to the development of novel therapies for heart valve diseases.

References

SHOWING 1-10 OF 50 REFERENCES

Agonism at 5-HT2B receptors is not a class effect of the ergolines.

Species differences in the pharmacology of the 5-hydroxytryptamine2 receptor: structurally specific differentiation by ergolines and tryptamines.

Examination of a series of ergolines revealed a distinct pattern in the species selectivity, with compounds that were unsubstituted at the N1 position of the ergoline nucleus showed higher affinity for the pig, squirrel monkey and human 5-HT2 receptors than for the rat.

Lisuride, a Dopamine Receptor Agonist With 5-HT2B Receptor Antagonist Properties: Absence of Cardiac Valvulopathy Adverse Drug Reaction Reports Supports the Concept of a Crucial Role for 5-HT2B Receptor Agonism in Cardiac Valvular Fibrosis

The data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.

Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine.

It is proposed that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or5-HT released from carcinoid tumors (with or without accompanying 5- HT(2A) receptor activation) may contribute to valvial fibroplasia in humans.

3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro.

It is found that long-term MDMA use could lead to the development of fenfluramine-like VHD, and the necessity of screening current and future drugs at h5-HT2B receptors for agonist actions before their use in humans is underscored.

Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. III. Agonist and Antagonist Properties at Serotonin, 5-HT1 and 5-HT2, Receptor Subtypes

Antiparkinson agents display markedly different patterns of agonist and antagonist properties at multiple 5-HT receptor subtypes, although all show modest (agonist) activity at5-HT1A sites, and their contrasting actions at 5-ht2A and 5- HT2C sites may be of particular significance to their functional profiles in vivo.

Pharmacological characterisation of human 5-HT2 receptor subtypes.

Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications

It is suggested that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at5-HT1B receptors.

Dopamine D2 receptor binding sites for agonists. A tetrahedral model.

A tetrahedral model is proposed; this has two sites for agonist attachment, the extremities of the sites being separated by 8 A, and their functional groups directed between 15 degrees and 30 degrees off the orthogonal from the receptor surface.